DESCRIPTION: (Applicant's Abstract) Although studies with humans confirm that there is a typical progression from tobacco and alcohol through marijuana to other drugs such as cocaine and heroin (the "gateway" hypothesis), no data exist on whether this is a purely social phenomenon, or whether there are underlying neurobiological substrates for this drug progression. Recent work on common substrates for different addictive drugs, and on drug interactions, make it plausible that there may be a biological component to drug progression. At least three possible such mechanisms may exist: (1) use of one drug may alter brain substrates [persistently] in such a way that later use of another drug is more reinforcing, (2) withdrawal from one drug may trigger behavior to seek relief from those symptoms, including consumption of another drug, or (3) cues conditioned to the use of one drug may elicit cravings which can be satisfied by another drug. Using adolescent rats as subjects, we propose to attempt an animal model of adolescent drug progression, and to determine whether any of the above three alternatives may underlie such progression. Subjects will be preexposed to alcohol during the juvenile period, and later evaluated on three tests (schedule-induced polydipsia of cocaine solution, cumulative cocaine dosing effects on activity, and conditioned place preference) to determine if reactions to cocaine are altered in any of three conditions: during the acute withdrawal phase from alcohol, long after acute withdrawal is concluded, and in the presence of cues formerly associated with alcohol. The proposed work will be the first attempt to develop an animal model of drug progression, and may have implications for both understanding and treatment of adolescent substance abuse, as well as continuing to define the plasticity of the CNS during later development.